Specific conformational changes of plasminogen induced by chloride ions, 6-aminohexanoic acid and benzamidine, but not the overall openness of plasminogen regulate, production of biologically active angiostatins. Biochem J 2005 Dec 15;392(Pt 3):703-12
Date
08/16/2005Pubmed ID
16097950Pubmed Central ID
PMC1316312DOI
10.1042/BJ20050907Scopus ID
2-s2.0-29644447174 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
The overall conformation of plasminogen depends upon the presence of anions and molecules such as AHA (6-aminohexanoic acid) and BZ (benzamidine). The purpose of the present study was to determine the effect of conformation on the initial and secondary cleavages of plasminogen to generate active angiostatins. Plasminogen was digested with the physiologically relevant neutrophil elastase in one of the four Tris/acetate buffers: buffer alone or buffer plus NaCl, AHA or BZ. The initial cleavage of Glu1-plasminogen was much slower in the tight NaCl-induced alpha-conformation, fastest in the intermediate BZ-induced beta-conformation and intermediate both in the control and in the AHA-induced open gamma-conformation. Although the buffer system determined the relative amounts of the initial cleavage products, the same four cleavage sites were utilized under all conditions. A fifth major initial cleavage within the protease domain was observed in the presence of BZ. N-terminal peptide cleavage required for angiostatin formation occurred as either the initial or the secondary cleavage. Angiostatins were generated fastest in the presence of BZ and slowest in the presence of NaCl. Both the initial and secondary cleavages were affected by the modifying agents, indicating that they influence the conformation of both Glu-plasminogen and the initial cleavage products. The angiostatins produced under the different conditions inhibited proliferation of human umbilical-vein endothelial cells. These results suggest that plasminogen conversion into active angiostatins is dependent more on the specific conformation changes induced by the various modifying reagents rather than on the overall openness of the molecule.
Author List
Warejcka DJ, Twining SSAuthor
Sally S. Twining PhD Assistant Dean, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Aminocaproic AcidAngiostatins
Benzamidines
Cell Line
Cell Proliferation
Chlorides
Endothelial Cells
Humans
Neutrophils
Pancreatic Elastase
Plasminogen
Protein Conformation
